Hostname: page-component-cd9895bd7-p9bg8 Total loading time: 0 Render date: 2024-12-30T19:38:02.742Z Has data issue: false hasContentIssue false

Genistein-induced apoptosis in MCF-7 cells involves changes in Bak and Bcl-x without evidence of anti-oestrogenic effects

Published online by Cambridge University Press:  09 March 2007

Lai See Po
Affiliation:
Department of Biochemistry, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong
Thomas T. Wang
Affiliation:
US Department of Agriculture, Beltsville Human Nutrition Research Center, Phytonutrients Laboratory, Beltsville, MD 20705, USA
Zhen-Yu Chen
Affiliation:
Food and Nutritional Sciences Programme, The Chinese University of Hong Kong, Shatin NT, Hong Kong
Lai K. Leung*
Affiliation:
Food and Nutritional Sciences Programme, The Chinese University of Hong Kong, Shatin NT, Hong Kong
*
*Corresponding author: Dr Lai K. Leung, fax +852 2603 7732, [email protected]
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

South-east Asian women have a lower rate of breast cancer compared with their counterparts in western countries and the difference in soyabean consumption has been claimed to be a major contributing factor. Genistein is the most studied phytochemical in the soyabean. An anti-oestrogenic effect is believed to play a crucial part in its chemopreventive mechanism. In the present study, we expressed oestrogen receptor (OR) in an OR-negative cell line, HepG2, to investigate the pro- and anti-oestrogenic effect of genistein on the OR transcriptional activity. Genistein by itself had an estimated concentration that induced 50 % of the maximum response (EC50) of 2·5 μM FOR THE BINDING TO OR-α. IN THESE EXPERIMENTS, GENISTEIN CONCENTRATION AS HIGH AS 50 μM could not reduce the oestrogen response element-driven luciferase activities initiated by oestradiol. Instead, genistein potentiated the OR transactivational activity while cell death was detected. On the other hand, an increased Bak and a reduced Bcl-x(L) was observed at 50 μm-genistein by Western analysis. The combined effect of these two proteins could be important in the apoptotic process. Since plasma genistein >50 μm has never been documented following consuming of soyabean or soyabean products, the present study does not support the notion that dietary soyabean exerts its chemopreventive effect through antagonizing OR.

Type
Research Article
Copyright
Copyright © The Nutrition Society 2002

References

Allred, D & Mohsin, SK (2000) Biological features of human premalignant breast disease. In Diseases of the Breast, pp. 355366 [Harris, JR, editor]. Philadelphia, PA: Lippincott Williams & Wilkins.Google Scholar
An, J, Tzagarakis-Foster, C, Scharschmidt, TC, Lomri, N & Leitman, DC (2001) Estrogen receptor β-selective transcriptional activity and recruitment of coregulators by phytoestrogens. Journal of Biological Chemistry 276, 1780817814.CrossRefGoogle ScholarPubMed
Arai, Y, Uehara, M, Sato, Y, Kimira, M, Eboshida, A, Adlercreutz, H & Watanabe, S (2000) Comparison of isoflavones among dietary intake plasma concentration and urinary excretion for accurate estimation of phytoestrogen intake. Journal of Epidemiology 10, 127135.CrossRefGoogle ScholarPubMed
Barkhem, T, Andersson-Ross, C, Hoglund, M & Nilsson, S (1997) Characterization of the estrogenicity of tamoxifen and raloxifene in HepG2 cells: regulation of gene expression from an ERE controlled reporter vector versus regulation of the endogenous SHBG and presenilin 2 genes. Journal of Steroid Biochemistry and Molecular Biology 62, 5364.CrossRefGoogle Scholar
Barnes, S (1995) Effect of genistein on in vitro and in vivo models of cancer. Journal of Nutrition 125, 777S783S.Google ScholarPubMed
Batistuzzo de Medeiros, SR, Krey, G, Hihi, AK & Wahli, W (1997) Functional interactions between the estrogen receptor and the transcription activator Sp1 regulate the estrogen-dependent transcriptional activity of the vitellogenin A1 io promoter. Journal of Biological Chemistry 272, 1825018260.CrossRefGoogle ScholarPubMed
Breinholt, V & Larsen, JC (1998) Detection of weak estrogenic flavonoids using a recombinant yeast strain and a modified MCF-7 cell proliferation assay. Chemical Research in Toxicology 11, 622629.CrossRefGoogle Scholar
Casanova, M, You, L, Gaido, KW, Archibeque-Engle, S, Janszen, DN & Heck, H d'A (1999) Developmental effects of dietary phytoestrogens in Sprague-Dawley rats and interactions of genistein and daidzein with rat estrogen receptors α and β in vitro. Toxicological Sciences 51, 236244.CrossRefGoogle ScholarPubMed
Ciocca, DR & Elledge, R (2000) Molecular markers for predicting response to tamoxifen in breast cancer patients. Endocrine 13, 110.CrossRefGoogle ScholarPubMed
Dechering, K, Boersma, C & Mosselman, S (2000) Estrogen receptors alpha and beta: two receptors of a kind? Current Medicinal Chemistry 7, 561576.CrossRefGoogle ScholarPubMed
Fioravanti, L, Cappelletti, V, Miodini, R, Ronchi, E, Brivio, M & Di Fronzo, G (1998) Genistein in the control of breast cancer cell growth: insights into the mechanism of action in vitro. Cancer Letters 130, 143152.CrossRefGoogle ScholarPubMed
Hall, JM, Couse, JF & Korach, KS (2001) The multifaceted mechanisms of estradiol and estrogen receptor signalling. Journal of Biological Chemistry 276, 3686936872.CrossRefGoogle Scholar
Hansen, MN, Nielsen, EE & Berg, K (1989) Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. Journal of Immunological Methods 119, 203210.CrossRefGoogle ScholarPubMed
Kuiper, GJM, Carlsson, B, Grandien, K, Enmark, E, Haggblad, J & Gustafsson, J-K (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology 138, 863870.CrossRefGoogle ScholarPubMed
Kuo, S-M (1997) Dietary flavonoid and cancer prevention: evidence and potential mechanism. Critical Reviews in Oncogenesis 8, 4769.CrossRefGoogle ScholarPubMed
Lamartiniere, CA (2000) Protection against breast cancer with genistein: a component of soy. American Journal of Clinical Nutrition 71 Suppl., 1705S1707S.CrossRefGoogle ScholarPubMed
Lamartiniere, CA, Moore, JB, Brown, NM, Thompson, R, Hardin, MJ & Barnes, S (1995 a) Genistein suppresses mammary cancer in rats. Carcinogenesis 16, 28332840.CrossRefGoogle ScholarPubMed
Lamartiniere, CA, Moore, J, Holland, MB & Barnes, S (1995 b) Neonatal genistein chemoprevents mammary carcinogenesis. Proceedings of the Society for Experimental Biology and Medicine 208, 120123.CrossRefGoogle Scholar
Le Bail, JC, Varnat, F, Nicolas, JC & Habrioux, G (1998) Estrogenic and anti-proliferative activities on MCF-7 human breast cancer cells by flavonoids. Cancer Letters 130, 209216.CrossRefGoogle Scholar
Leung, LK, Lin, D & Wang, TTY (1998) Regulation of death promoter Bak expression by cell density and 17β-estradiol in MCF-7 cells. Cancer Letters 124, 16.CrossRefGoogle ScholarPubMed
Leung, LK & Wang, TT (2000) Bcl-2 is not reduced in the death of MCF-7 cells at low genistein concentration. Journal of Nutrition 130, 29222926.CrossRefGoogle Scholar
Makela, S, Santti, R, Salo, L & McLachlan, JA (1995) Phytoestrogens are partial estrogen agonists in the adult male mouse. Environmental Health Perspectives 103, Suppl., 123127.Google ScholarPubMed
Miodini, P, Fioravanti, L, Di Fronzo, G & Cappelletti, V (1999) The two phyto-oestrogens genistein and quercetin exert different effects on oestrogen receptor function. British Journal of Cancer 80, 11501155.CrossRefGoogle ScholarPubMed
Montano, MM & Katzenellenbogen, BS (1997) The quinone reductase gene: a unique estrogen receptor-regulated gene that is activated by antiestrogens. Proceedings of National Academy of Sciences USA 94, 25812586.CrossRefGoogle ScholarPubMed
Nenci, I, Marchetti, E & Querzoli, P (1988) Commentary on human mammary pre-neoplasia. The estrogen receptor-promotion hypothesis. Journal of Steroid Biochemistry B 105106.CrossRefGoogle Scholar
Paech, K, Webb, P, Kuiper, GG, Nilsson, S, Gustafsson, J, Kushner, PJ & Scanlan, TS (1997) Differential ligand activation of estrogen receptors ER alpha and ER beta at AP1 sites. Science 277, 15081510.CrossRefGoogle Scholar
Perillo, B, Sasso, A, Abbondanza, C & Palumbo, G (2000) 17β-Estradiol inhibits apoptosis in MCF-7 cells inducing bcl-2 expression via two estrogen-responsive elements present in the coding sequence. Molecular Cell Biology 20, 28902901.CrossRefGoogle ScholarPubMed
Peterson, G & Barnes, S (1991) Genistein inhibition of the growth of human breast cancer cells: independence from estrogen receptors and the multi-drug resistance gene. Biochemical and Biophysical Research Communications 179, 661667.CrossRefGoogle ScholarPubMed
Pike, AC, Brzozowski, AM & Hubbard, RE (2000) A structural biologist's view of the oestrogen receptor. Journal of Steroid Biochemistry and Molecular Biology 74, 261268.CrossRefGoogle ScholarPubMed
Shao, Z-M, Alpaugh, ML, Fontana, JA & Barsky, SH (1998) Genistein inhibits proliferation similarly in estrogen receptor-positive and negative human breast carcinoma cell lines characterized by p21WAF1/CIP1 induction G2/M arrest and apoptosis. Journal of Cell Biochemistry 69, 4454.3.0.CO;2-V>CrossRefGoogle Scholar
Sheng, ZM, Marchetti, A, Buttitta, F, Champeme, MH, Campani, D, Bistocchi, M, Lidereau, R & Callahan, R (1996) Multiple regions of chromosome 6q affected by loss of heterozygocity in primary human breast carcinomas. British Journal of Cancer 73, 144147.CrossRefGoogle Scholar
So, FV, Guthrie, N, Chambers, AF & Carroll, KK (1997) Inhibition of proliferation of estrogen receptor-positive MCF-7 human breast cancer cells by flavonoids in the presence and absence of excess estrogen. Cancer Letters 112, 127133.CrossRefGoogle ScholarPubMed
Suo, Z, Berner, HS, Risberg, B, Karlsson, MG & Nesland, JM (2001) Estrogen receptor-alpha and C-ERBB-4 expression in breast carcinomas. Virchows Archiv 439, 6269.CrossRefGoogle ScholarPubMed
Tong, D, Schuster, E, Seifert, M, Czerwenka, K, Leodolter, S & Zeillinger, R (2002) Expression of estrogen receptor beta isoforms in human breast cancer tissues and cell lines. Breast Cancer Research and Treatment 71, 249255.CrossRefGoogle ScholarPubMed
Wang, C & Kurzer, MS (1997) Phytoestrogen concentration determines effects on DNA synthesis in human breast cancer cells. Nutrition and Cancer 28, 236247.CrossRefGoogle ScholarPubMed
Wang, TT, Sathyamoorthy, N & Phang, JM (1996) Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis 17, 271275.CrossRefGoogle ScholarPubMed
Wang, TTY & Phang, JM (1995) Effects of estrogen on apoptotic pathways in human breast cancer cell line MCF-7. Cancer Research 55, 39023907.Google ScholarPubMed
Yang, NN, Venugopalan, M, Hardikar, S & Glasebrook, A (1996) Identification of an estrogen response element activated by metabolites of 17beta-estradiol and raloxifene. Science 273, 12221225.CrossRefGoogle ScholarPubMed
Ziegler, RG, Hoover, RN, Pike, MC, Hidesheim, AA, Nomura, AM, West, DDW, Wu-Williams, AAH, Kolonel, LN, Horn-Ross, PL & Rosenthal, JF (1993) Migration patterns and breast cancer risk in Asian-American women. Journal of National Cancer Institute 85, 18191827.CrossRefGoogle ScholarPubMed